Chalcone is a member or derivative of the phenylypropanoids, a large group of phenolic compounds synthesized only in plants, and predominantly derived from the aromatic amino acid phenylalanine. Phenylpropanoids and their derivatives perform diverse physiological functions in plants, and are represented by the polymeric lignins, the coumarins, suberins, stilbenes and flavonoids, as well as the chalcones, sometimes considered a sub-class of the flavonoids. In the predominant form of lignins, phenylpropanoids are second only to cellulose among the bio-molecules in total biosphere abundance. Lignins have a primarily structural role, but many compounds in this versatile group are biochemically active. The flavonoids, for example serve in many species as attractants of pollinators, UV protectors, insect repellents, signalling molecules and antibiotics, while the coumarins and stilbenes are implicated in the defense response of plants to pathogen ingress via their anti-microbial function effect.
Considering the other leg of the background of the present invention, angiogenesis may be defined as the development of a blood supply to a given area of tissue. The development of a blood supply may be part of normal embryonic development, represent the revascularization of a wound bed, or involve the stimulation of vessel growth by inflammatory or malignant cells. Sometimes angiogenesis is defined as the process through which tumors or inflammatory conditions derive a blood supply through the generation of microvessels. Although it may seem unremarkable that new growth of soft tissue requires new vascularization, the concept of angiogenesis as a key component of tissue growth and in particular, a key point of intervention in pathological tissue growth, had initially met with skepticism. By now the idea is well accepted.
Tumors need to induce formation of blood vessels to grow beyond a small size. A small tumor can use diffusion from nearby capillaries as its source of oxygenation, nutrition, and waste removal. However, once a tumor exceeds a critical mass, the center of the tumor becomes necrotic, because these crucial functions are no longer available. When a tumor gains the ability to generate new blood vessels, perfusion of a larger tumor mass is possible. The ability of malignant cells to form a large tumor and to metastasize is accompanied by decreased cellular differentiation and increased ability to produce angiogenic factors. Hence there is a strong interest in compounds that block angiogenesis and interrupt the growth process of malignant tumors, inflammatory lesions and benign neoplasms, as well as in compounds which stimulate cellular differentiation, and impede metastasis.
A tumor's ability to become neovascularized permits rapid tumor growth and increases the likelihood of metastases; the transition from a quiescent tumor to an invasive tumor is accompanied by the crucial acquisition of angiogenic properties. The critical point may be characterized as the activation of a specific angiogenic switch. The phenotypic change from quiescence to virulence likely requires a change in the balance of angiogenic simulators and angiogenic inhibitors. The nature of the angiogenic switch is not known, however, growth factors and signal transduction are expected to be key components in the investigation of angiogenic regulatory mechanisms.
The first angiogenesis factor isolated was basic fibroblast growth factor (bFGF). Others include vascular endothelial growth factor (VEGF), interleukin-8, hepatocyte growth factor, platelet derived endothelial growth factor (PD-ECGF), and corticotropin-releasing hormone (CRH). The discovery of endogenous angiogenesis simulators naturally led researchers to ask whether there existed endogenous angiogenesis inhibitors. Interferon-alpha, which inhibits the replication of primary endothelial cells, was the first endogenous angiogenesis inhibitor discovered. Other naturally occurring small molecules which have been discovered to have anti-angiogenic activity include the retinoids and curcumin, a small molecular weight compound which is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. A summary of some major known angiogenesis stimulators and inhibitors is shown below.
Angiogenesis SimulatorsAngiogenesis InhibitorsBasic fibroblast growth factor (bFGF)AngiostatinVascular endothelial growth factor (VEGF)EndostatinProstaglandin E2CurcuminHepatocyte growth factorFumagillin derivativesProliferinProliferin-related peptideNitric oxideNitric oxide inhibitorsIntegrins (αvβ3, αvβ4)Phosphatidylinositol-3-kinase inhibitorsCorticotropin-releasing hormoneThalidomideInterleukin-8Interleukin-12Platelet derived endothelial growth factorFarnesyltransferaseinhibitorsprotaglandinretinoidsalpha interferon
Among the angiogenisis inhibitors, retinoids (vitamin A and its derivatives) play an important role in the development and differentiation of epidermal cells, as well as in reversing precancerous lesions. A number of references disclose retinoids being used in cancer prophylaxis and as inducers of cell differentiation. Kizaki et al., Seminars in Oncology 19(1):95-105(1992), for example, report that retinoids are potential anti-carcinogenic agents in many experimental models and that they inhibit growth and induce differentiation in transformed neoplastic cells. Unfortunately, the retinoids have a significant level of toxicity and administration of the known retinoid agents at therapeutic doses may be associated with undesirable side effects including headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dylipidemias, skin irritation, headache and hepatotoxicity. Accordingly, there exists a need to provide novel compounds having retinoid activity but which have less toxicity and/or side effects.
Chalcone compounds (3-oxo-1-propenyl derivatives) are sometimes classified as derivatives of the retinoids, and also of the flavones or flavonoids. Some flavones and chalcones have been found to have anti-tumor properties. Compounds related to coumarin, a flavone isolate from the widely used spice turmeric, are known to inhibit the carcinogenicity of carcinogens: Coumarin has been tested for treatment of melanoma. Certain chalcones and flavonoids, including biochanin A, are also known to exhibit anti-mitotic action in inhibiting cell division; e.g. in Shibata, Anti-tumorgenic chalcones, Stem Cells, 12:44-62, 1994; Edwards et al., Chalcones: A New Class of Antimitotic Agents, J. Med. Chem., 33:1948-1954, 1990; and Varma, Dietary Bioflavonoids, Chalcones and Related Alkenones in Prevention and Treatment of Cancer, Nutrition, 12; 643 (1996).